1. The purine dideoxynucleosides 2'-Beta-fluoro-2',3'-dideoxyadenosine (2'-Beta-F-ddAdo), 2'-Beta-fluoro-2',3'-dideoxyinosine (2'-Beta-F-ddIno), and 2'-Beta-fluoro-2',3'-dideoxyguanosine (2'-Beta-F-ddGuo) are active inhibitors of the replication of the human immunodeficiency virus (HIV) in the ATH8 assay system. 2'-Beta-F-ddAdo and 2'-Beta-F-ddIno show activity and potency equivalent to that of their respective parent compounds, 2',3'-dideoxyadenosine (ddAdo) and 2',3'-dideoxyinosine (ddIno). The fluorinated compounds lack the acid and enzymatic instability of ddAdo, ddIno and ddGuo. Since inhibitors of inosine monophosphate dehydrogenase (IMPD) such as ribavirin and tiazofurin stimulate the 5'-phosphorylation and consequently the anti-HIV activity of two of the non-fluorinated parent compounds (ddIno, ddGuo), we have undertaken a study in MOLT-4 cells to determine whether a similar stimulatory effect is observed with the 2'-beta-fluorinated analogs. The 5'-phosphorylation and antiviral activity of all the fluoro compounds was found to be enhanced by low levels (10 muM) of either ribavirin or tiazofurin. 2. Studies on the intracellular pharmacology of 2',3'- dideoxyinosine have continued in human T-cell systems. Formation of ddATP from ddIno was rapid and concentration-dependent, whereas rates of removal of ddATP from cells were extremely slow (t+ = 25-40 hr). The long half-time of disappearance may permit effective clinical dosage with infrequent administration of the parent drug. 3. In studies with ddCyd, the metabolites 2',3'-dideoxycytidine diphosphocholine and 2',3'- dideoxycytidine diphosphoethanolamine have been synthesized and the identity of the synthetic and biologically-generated metabolites confirmed by mass spectrometry. All ddCyd analogues studied to date have been found to generate similar phosphodiester metabolites.